With the development of productivity and quality of life, metabolic syndrome, characterized by obesity, anti-insulin (type II diabetes), lipid metabolism disorder, and hypertension, occurs throughout the world, and threatens human health greatly due to excessive intake of fats and proteins, In addition to association with the genetic characteristics, age, sex, physiological characteristics, nutritional status, diet habits, etc. of individuals, metabolism syndrome is also involved in the broken of balances of lipid metabolism, energy, and carbohydrate metabolism in vivo. Thus, a therapeutic regimen aiming to maintain the balances of energy, fats and carbohydrates in vivo becomes an effective method for treating metabolism syndrome. Nuclear receptors (NRs) tends to a focus of researches as it plays a critical role in maintaining the balance of energy, and the balances of fats and carbohydrates in cells, even in the whole individual. Nuclear receptors can regulate transcription systems of responsive genes, and thus exerting their physiological activity only after being activated by various physiological ligands (e.g. saturated and unsaturated fatty acids, metabolites and various synthetic compounds thereof) (Kasuga, J. et al., Bioorg. Med. Chem. 2007, 15, 5177-5190).
In the family of nuclear receptors, peroxisome proliferator-activated receptors (PPARs), nuclear transcription factors activated by ligands, have attracted the attention from the researchers for more than ten years, and are important regulatory factors in metabolism syndrome (Guan, Y. J. Am. Soc. Nephrol, 2004, 15, 2801-2815). Therefore, PPARs play an important role in the pathogenesis, development, treatment, and prevention of diseases, e.g. insulin resistance, impaired glucose tolerance, type II diabetes, obesity, hyperlipidemia, hypertension, cardiovascular diseases, artherosclerosis, etc.
PPARs are classified into three subtypes: PPARα, PPARδ, and PPARγ, which regulate expression of gene by binding to specific DNA sequences (Berger, J. et al., The Journal of Biological Chemistry, 1999, 274 (10), 6718-6725). PPARα is mainly expressed in liver, heart, intestinal tract, kidney, and macrophage, and can increase the metabolism of fatty acids, alleviate inflammatory response of macrophage, and reduce low density lipoprotein cholesterol, after being activated; PPARγ is expressed in adipocyte, placentoma, and other tissues, and not only can reduce blood glucose and increase insulin sensitivity but also plays a critical role in lipid metabolism, cytokine inhibition, anti-inflammation, immune regulation, blood pressure regulation, etc., after being activated (Kasuga, J. et al., Bioorg. Med. Chem. 2007, 15, 5177-5190). Relative to the other two subtypes, the physiological function of PPARδ is unknown so far. However, recent researches on animal models for pharmacology experiments show that PPARδ can increase the catabolism of fatty acid and energy uncoupling in adipose tissues and muscles, and inhibit macrophage-derived inflammation. By controlling weight gain, increasing tolerance of human body, increasing insulin sensitivity, and improving artherosclerosis in various aspects, ligands of PPARδ may thus become an effective medicament for treating hyperlipidemia, obesity, insulin resistance, and artherosclerosis.
Nowadays, none of “three channel” agonist having effect on all of PPARα, PPARδ, and PPARγ is commercially available as a therapeutic agent throughout the world. The “three channel” agonist of PPARα, PPARδ, and PPARγ developed by the inventors can be used in the treatment of metabolism syndrome which is mainly characterized by diabetes. It has a similar function as glitazones or other insulin sensitizers, but can be applied more widely. Although PPARγ agonists, glitazones can increase the sensitivity to insulin, recent clinical results show that it might increase the risk of cardiovascular diseases. Moreover, glitazones have further common side effects, including weight gain and liver toxicity. Therefore, the inventors make great efforts to find a novel medicament which not only can treat diabetes but also have a certain protection effect on cardiovascular.
The research and development of novel medicaments for metabolism syndrome have been a focus in many pharmaceutical companies. Chinese pharmaceutical companies are also competitively focusing their researches on new targets in the development of medicines for diabetes. Therefore, it will be of great clinical significance to provide novel compounds having activating effect on peroxisome proliferator-activated receptors (PPARα, PPARδ, and PPARγ).